The present invention concerns pharmaceutical compositions which may be used in the treatment of cancer, especially carcinoma, or illnesses which arise due to an elevated cell proliferation. The compounds which are active in the compositions according to the present invention are acyl derivatives of aromatic aldehydes, especially arylidene diesters and alkoxyarylidene esters.
It is known from EP215395, J63264411, J88009490, J55069510 and EPO283139 that aromatic aldehydes and derivatives thereof have an anti-cancer effect. These compounds exert an inhibitory action on the protein synthesis of the cells.
In solid tumors this reduced protein synthesis may result in a lack of vital proteins which lead to cell death. In normal cells there is a potential capacity for protein synthesis which is higher than in most cancer cells of solid tumors. This is demonstrated by comparison of the cell cycle duration in normal stem cells, which is often below 10 h, with that of most cancer cells of solid tumors, which is typically 30-150 h (see Gavosto and Pileri in: The Cell Cycle and Cancer. Ed.: Baserga, Marcel Dekker Inc., N.Y. 1971, pp 99). Since cells, as an average, double their protein during a cell cycle, this means that protein accumulation is higher in growth-stimulated normal cells than in most types of cancer cells.
Keeping in mind this difference between normal and cancer cells, there is another difference of similar importance: while normal cells respond to growth-regulatory stimuli, cancer cells have a reduced or no such response. Thus, while normal cells, under ordinary growth conditions, may have a reserve growth potential, cancer cells have little or no such reserve. If a protein synthesis inhibition is imposed continuously over a long period of time on normal cells as well as on cancer cells it is probable that the two different types of cells will respond differently: Normal tissue may take into use some of its reserve growth potential and thereby maintain normal cell production. Cancer tissue however, have little or no such reserve. At the same time the rate of protein accumulation in most cancer cells is rather low (i.e. protein synthesis is only slightly greater than protein degradation). Therefore the protein synthesis inhibition may be just enough to render the tumor tissue imbalanced with respect to protein accumulation, giving as a result a negative balance for certain proteins. During continuous treatment for several days this will result in cell inactivation and necrosis in the tumor tissue while normal tissue is unharmed.
To date, the most tested compound inducing reversible protein synthesis inhibition and displaying anti-cancer activity is zilacorb(.sup.2 H) [5,6-benzylidene-d.sub.1 -ascorbic acid]. The protein synthesis inhibiting activity of this prior art compound is described in detail by Pettersen et al. (Anticancer Res., 11: 1077-1082,1991) and in EP0283139. Zilacorb(.sup.2 H) induces tumor necrosis in vivo in human tumor xenografts in nude mice (Pettersen et al., Br. J. Cancer, 67:650-656,1993), and the compound is currently being tested in Phase I and Phase II clinical trials. Since zilascorb(.sup.2 H) is a derivate of an aromatic aldehyde, the activity of new compounds described in the present invention will be compared with that of zilascorb(.sup.2 H).
It is known from UK Patent application 9026080.3 that benzaldehyde compounds, previously known as anti-macer agents may be used for combatting diseases resulting from an abnormally elevated cell proliferation. Such compounds also exert an effect on cells having an abnormally elevated cellular proliferation rate, and accordingly the compounds may be used for the treatment of diseases such as psoriasis, inflammatory diseases, rheumatic diseases and allergic dermatologic reactions.
Dermatologic abnormalities such as psoriasis are often characterized by rapid turnover of the epidermis. While normal skin produces ca. 1250 new cells/day/cm.sup.2 of skin consisting of about 27,000 cells, psoriatic skin produces 35,000 new cells/day/cm.sup.2 from 52,000 cells. The cells involved in these diseases are however "normal" cells reproducing rapidly and repeatedly by cell division. While the renewal of normal skin cell s takes approximately 311 hours, this process is elevated to take about 10 to 36 hours for psoriatic skin.
It is known that aromatic aldehydes and certain acetal derivatives thereof have a growth-inhibitory effect on human cells which is by its nature reversible. Growth inhibition induced by these compounds is primarily due to a reduction in the protein synthesis by cells. (Pettersen et al., Eur.J.Clin. Oncol. 19, 935-940 (1983) and Cancer Res. 45, 2085-2091 (1985)). The inhibition of protein synthesis is only effective as long as these agents are present in the cellular microenvironment. The synthesis of cellular protein is, for instance, rapidly restored to its normal level within one hour from the time when the agent is removed from the cells.
This leads to the effect that the normal cells are left without damage after treatment with the above compounds. Furthermore, the resulting inhibition of protein synthesis induces a prolonged cell cycle duration, such that a reduction of the cell production as well as a reduction of protein synthesis is achieved during treatment.
Examples of diseases which may be treated by the above compositions are rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosis (SLE), discoid lupus erythematosis (DLE), acne, Bechterew's arthritis, progressive systemic sclerosis (PSS) and seborrhea.